Nitroalkene non steroidal anti-inflammatory drugs (NA-NSAIDs) and methods of treating inflammation related conditions

ABSTRACT

Nitroalkene non-steroidal anti-inflammatory compounds, pharmaceutical compositions thereof, and methods of treating inflammation related conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to co-pending U.S. Non-Provisionalapplication Ser. No. 15/784,685 filed on Oct. 16, 2017 and InternationalApplication No. PCT/IB2017/056417 filed on Oct. 16, 2017, both of whichclaim priority to U.S. Provisional Application No. 62/408,459 filed onOct. 14, 2016 and U.S. Provisional Application No. 62/570,973 filed onOct. 11, 2017. U.S. Non-Provisional application Ser. No. 15/784,685,International Application No. PCT/IB2017/056417, U.S. ProvisionalApplication No. 62/408,459, and U.S. Provisional Application No.62/570,973 are all incorporated by reference in their entireties.

BACKGROUND

Common chronic inflammatory diseases (“CIDs”) such as, inter alia,atherosclerosis, type 2 diabetes, asthma, gouty arthritis, kidneydiseases, lupus, and inflammatory diseases of the central nervous system(“CNS”), pose a large risk and burden to afflicted patients because ofits long-term debilitating illness that results in increased mortalityand high health care costs. CIDs often involve a low-grade, controlled,and chronic systemic inflammatory state, which is generated by theactivation of the pro-inflammatory transcription factor NF-κB and theinflammasome (a cytosolic supramolecular platform responsible of theproduction of interleukin (IL) 1β and 18 (IL-1β, IL-18)). However, asopposed to short term acute inflammation or infections, which illicit animmediate healing response to overcome a disease, the slow systemicprogression of CIDs often preclude an adaptive healing response, whichleads to chronic disease sequelae. Currently, classical NSAIDs thatprovide analgesic (pain-killing) and antipyretic (fever-reducing)effects, and, in higher doses, anti-inflammatory effects, are notrecommended for the therapy of these diseases.

Thus, the scope of the present invention includes nitroalkene NSAIDcompounds and methods of treating inflammation related conditions, suchas low grade chronic inflammation that underlies most non-transmissibleCIDs.

SUMMARY

One embodiment within the scope of the invention is a compound ofFormula I:

wherein R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.

In another embodiment the invention is a compound of Formula II:

wherein R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt.

One embodiment within the scope of the invention is a compound ofFormula III:

where R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.

In another embodiment within the scope of the invention is a compound ofFormula IV:

where R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.

In another embodiment within the scope of the invention is a compound ofFormula V:

where R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.

One embodiment within the scope of the present invention is a method oftreating inflammation related conditions comprising administering to asubject in need thereof a therapeutically effective amount of anitroalkene nonsteroidal anti-inflammatory drug.

DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the spectrograph of a reaction of PARANA (30 μM) withbeta-mercaptoethanol (30 μM) in Phosphate Buffer 100 mM pH 7.4 followedspectrophotometrically (each spectra every 60 sec).

FIG. 2 depicts the spectrograph of a reaction of IBUNA (50 μM) withbeta-mercaptoethanol (250 μM) in Phosphate Buffer 100 mM pH 7.4 followedspectrophotometrically (each spectra every 60 sec).

FIG. 3 depicts the spectrograph of a reaction of FluFENA (12.5 μM) withbeta-mercaptoethanol (125 μM) in Phosphate Buffer 100 mM pH 7.4 followedspectrophotometrically (each spectra every 60 sec).

FIG. 4 depicts the spectrograph of a reaction of BANA (10 μM) withbeta-mercaptoethanol (30 μM) in Phosphate Buffer 100 mM pH 7.4 followedspectrophotometrically (each spectra every 60 sec).

FIG. 5 depicts the spectrograph of a reaction of PheNA (50 μM) withbeta-mercaptoethanol (500 μM) in Phosphate Buffer 100 mM pH 7.4 followedspectrophotometrically (each spectra every 60 sec).

FIG. 6 illustrates inflammasome modulation by BANA after stimulation byLPS (1st signal).

FIG. 7 illustrates inflammasome modulation by BANA after stimulation byATP (2nd signal).

FIG. 8 illustrates inflammasome modulation by FluFENA after stimulationby LPS (1st signal).

FIG. 9 illustrates inflammasome modulation by FluFENA after stimulationby ATP (2nd signal).

FIG. 10 illustrates inflammasome modulation by IBUNA after stimulationby LPS (1st signal).

FIG. 11 illustrates inflammasome modulation by IBUNA after stimulationby ATP (2nd signal).

FIG. 12 demonstrates in vivo inhibition of IL-1β release in LPS-inducedinflammatory response by BANA.

DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications that may be mentioned herein areincorporated by reference in their entirety. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “cell” is a reference to one or more cells and equivalents thereofknown to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 5% of the numericalvalue of the number with which it is being used. Therefore, about 50%means in the range of 45%-55%. “Administering” when used in conjunctionwith a therapeutic means to administer a therapeutic directly to asubject, whereby the agent positively impacts the target.“Administering” a composition may be accomplished by, for example,injection, oral administration, topical administration, or by thesemethods in combination with other known techniques. Such combinationtechniques include heating, radiation, ultrasound and the use ofdelivery agents. When a compound is provided in combination with one ormore other active agents (e.g. other anti-atherosclerotic agents such asthe class of statins), “administration” and its variants are eachunderstood to include concurrent and sequential provision of thecompound or salt and other agents.

By “pharmaceutically acceptable” it is meant the carrier, diluent,adjuvant, or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

“Composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to “pharmaceutical composition” is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier.

As used herein, the term “agent,” “active agent,” “therapeutic agent,”or “therapeutic” means a compound or composition utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. Furthermore, the term “agent,” “active agent,”“therapeutic agent,” or “therapeutic” encompasses a combination of oneor more of the compounds of the present invention.

A “therapeutically effective amount” or “effective amount” of acomposition is a predetermined amount calculated to achieve the desiredeffect, i.e., to inhibit, block, or reverse the activation, migration,proliferation, alteration of cellular function, and to preserve thenormal function of cells. The activity contemplated by the methodsdescribed herein includes both medical therapeutic and/or prophylactictreatment, as appropriate, and the compositions of the invention may beused to provide improvement in any of the conditions described. It isalso contemplated that the compositions described herein may beadministered to healthy subjects or individuals not exhibiting symptomsbut who may be at risk of developing a particular disorder. The specificdose of a compound administered according to this invention to obtaintherapeutic and/or prophylactic effects will, of course, be determinedby the particular circumstances surrounding the case, including, forexample, the compound administered, the route of administration, and thecondition being treated. However, it will be understood that the chosendosage ranges are not intended to limit the scope of the invention inany way. A therapeutically effective amount of compound of thisinvention is typically an amount such that when it is administered in aphysiologically tolerable excipient composition, it is sufficient toachieve an effective systemic concentration or local concentration inthe tissue.

The terms “treat,” “treated,” or “treating” as used herein refer to boththerapeutic treatment and prophylactic or preventative measures, whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or to obtain beneficialor desired clinical results. For the purposes of this invention,beneficial or desired results include, but are not limited to,alleviation of symptoms; diminishment of the extent of the condition,disorder, or disease; stabilization (i.e., not worsening) of the stateof the condition, disorder, or disease; delay in onset or slowing of theprogression of the condition, disorder, or disease; amelioration of thecondition, disorder, or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder, or disease.

The term “subject,” as used herein, describes an organism, includingmammals, to which treatment with the compositions and compoundsaccording to the subject disclosure can be administered. Mammalianspecies that can benefit from the disclosed methods include, but are notlimited to, apes, chimpanzees, orangutans, humans, monkeys; and otheranimals such as dogs, cats, horses, cattle, pigs, sheep, goats,chickens, mice, rats, guinea pigs, and hamsters. Typically, the subjectis a human.

The optical isomers with the scope of the present invention can beobtained by resolution of the racemic mixtures according to conventionalprocesses, for example by formation of diastereoisomeric salts bytreatment with an optically active base and then separation of themixture of diastereoisomers by crystallization, followed by liberationof the optically active bases from these salts. Another method calls forchiral separation of the enantiomers with the use of a chiralchromatography column optimized to maximize the separation of theenantiomers. Optimization of the chromatographic method of chiralresolution is routine for one of ordinary skill in the art. Yet anothermethod for isolating optical isomers is by distillation, crystallizationor sublimation if a physical property of the enantiomers is different.The optically active compounds within the scope of the present inventioncan also be obtained by utilizing optically active starting materials.The isomers may be in the form of a free acid, a free base, an ester ora salt.

Also included in the compounds within the scope of the present inventionand the stereoisomers are the pharmaceutically-acceptable salts thereof.The term “pharmaceutically-acceptable salts” embraces salts commonlyused to form alkali metal salts and to form additional salts of freeacids or free bases. The nature of the salt is not critical, providedthat it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts of compounds within thescope of the present invention may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoricacid. Appropriate organic acids may include aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes oforganic acids. Examples of such organic acids include formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydrobenzoic,phylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohyexylaminosuflonic, stearic, algenic, β-hydrobutyric,galactaric and galacturnoic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds within the scope of the presentinvention include metallic salts, such as salts made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc, or salts madefrom organic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, triethylamine,trimethylamine. All the listed salts of the corresponding compound ofthe invention may be prepared by conventional means known to one ofordinary skill in the art. One example of a conventional method of saltformation is by reacting the appropriate acid or base with a compoundswithin the scope of the present invention at various mole ratios.Another method is by using different mole ratios of the appropriate acidor base in various solvent systems to control the concentration of thedissociated species of a compound within the scope of the presentinvention to maximize salt formation. The present invention alsocontemplates crystalline forms of the salts described herein.

Crystalline forms of compounds within the scope of the presentinvention, may also include but are not limited to hydrates, solvates,and co-crystals. Crystalline solvates include solvents including but notlimited to the following: MeOH, EtOH, AcOH, EtOEt, AcOEt, acetone, DMSO,DMF, MeCN, CH₂Cl₂, CHCl₃, CCl₄, dioxane, THF, benzene, toluene,p-xylene, and hexane.

Crystalline hydrates and solvates may be stoichiometric as according tothe mole ratio of the water or organic solvent molecule to the compoundor salt thereof. The crystalline hydrate may also be non-stoichiometricdepending on the conditions of the unit cell which result in athermodynamically or kinetically stable crystal. Crystalline salts andco-crystals may also be stoichiometric or non-stoichiometric for reasonsstated above. One of skill in the art of crystallography understandsthat the components in the unit cell of a crystal may or may not bestoichiometric depending on the conditions that stabilize a crystal.

Administration and Compositions

The compounds and pharmaceutically-acceptable salts thereof can beadministered by means that produces contact of the active agent with theagent's site of action. They can be administered by conventional meansavailable for use in conjunction with pharmaceuticals in a dosage rangeof 0.001 to 1000 mg/kg of mammal (e.g. human) body weight per day in asingle dose or in divided doses. One dosage range is 0.01 to 500 mg/kgbody weight per day orally in a single dose or in divided doses.Administration can be delivered as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, buttypically are administered with a pharmaceutically acceptable excipientselected on the basis of the chosen route of administration and standardpharmaceutical practice.

Compounds can be administered by one or more ways. For example, thefollowing routes may be utilized: oral, parenteral (includingsubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques), inhalation, buccal, sublingual, orrectal, in the form of a unit dosage of a pharmaceutical compositioncontaining an effective amount of the compound and optionally incombination with one or more pharmaceutically-acceptable excipients suchas stabilizers, anti-oxidants, lubricants, bulking agents, fillers,carriers, adjuvants, vehicles, diluents and other readily knownexcipients in standard pharmaceutical practice.

Liquid preparations suitable for oral administration (e.g. suspensions,syrups, elixirs and other similar liquids) can employ media such aswater, glycols, oils, alcohols, and the like. Solid preparationssuitable for oral administration (e.g. powders, pills, capsules andtablets) can employ solid excipients such as starches, sugars, kaolin,lubricants, binders, disintegrating agents, antioxidants and the like.

Parenteral compositions typically employ sterile water as a carrier andoptionally other ingredients, such as solubility aids. Injectablesolutions can be prepared, for example, using a carrier comprising asaline solution, a glucose solution or a solution containing a mixtureof saline and glucose. Further guidance for methods suitable for use inpreparing pharmaceutical compositions is provided in Remington: TheScience and Practice of Pharmacy, 21^(st) edition (Lippincott Williams &Wilkins, 2006).

Therapeutic compounds can be administered orally in a dosage range ofabout 0.001 to 1000 mg/kg of mammal (e.g. human) body weight per day ina single dose or in divided doses. One dosage range is about 0.01 to 500mg/kg body weight per day orally in a single dose or in divided doses.For oral administration, the compositions can be provided in the form oftablets or capsules containing about 1.0 to 500 mg of the activeingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150,200, 250, 300, 400, 500, and 750 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy. In view of the factors affecting the specific doselevel and frequency it is contemplated that the dose frequency can rangefrom multiple doses daily to monthly dosages. The preferred dosefrequency ranges from twice a day to every two weeks. A more preferreddose frequency ranges from twice a day to weekly. A most preferred dosefrequency ranges from twice a day to twice a week.

In the methods of various embodiments, pharmaceutical compositionsincluding the active agent can be administered to a subject in an“effective amount.” An effective amount may be any amount that providesa beneficial effect to the patient, and in particular embodiments, theeffective amount is an amount that may treat inflammation relatedconditions such as, but not limited to, CIDs.

Pharmaceutical formulations containing the compounds of the inventionand a suitable carrier can be in various forms including, but notlimited to, solids, solutions, powders, fluid emulsions, fluidsuspensions, semi-solids, and dry powders including an effective amountof an the active agent of the invention. It is also known in the artthat the active ingredients can be contained in such formulations withpharmaceutically acceptable diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,antioxidants, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) both of which are herebyincorporated by reference in their entireties can be consulted.

Other embodiments of the invention include the active agent prepared asdescribed above which are formulated as a solid dosage form for oraladministration including capsules, tablets, pills, powders, andgranules. In such embodiments, the active compound may be admixed withone or more inert diluent such as sucrose, lactose, or starch. Suchdosage forms may also comprise, as in normal practice, additionalsubstances other than inert diluents, e.g., lubricating agents such asmagnesium stearate. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents and can additionally beprepared with enteric coatings.

In another exemplary embodiment, an oily preparation of an active agentprepared as described above may be lyophilized to form a solid that maybe mixed with one or more pharmaceutically acceptable excipient, carrieror diluent to form a tablet, and in yet another embodiment, the activeagent may be crystallized to from a solid which may be combined with apharmaceutically acceptable excipient, carrier or diluent to form atablet.

The means and methods for tableting are known in the art and one ofordinary skill in the art can refer to various references for guidance.For example, Pharmaceutical Manufacturing Handbook: Production andProcesses, Shayne Cox Gad, John Wiley & Sons, Inc., Hoboken, N.J.(2008), which is hereby incorporated by reference in its entirety can beconsulted.

Further embodiments which may be useful for oral administration of theactive agent include liquid dosage forms. In such embodiments, a liquiddosage may include a pharmaceutically acceptable emulsion, solution,suspension, syrup, and elixir containing inert diluents commonly used inthe art, such as water. Such compositions may also comprise adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring, and perfuming agents. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt. Other suitable diluents include, but are notlimited to those described below:

Vegetable oil: As used herein, the term “vegetable oil” refers to acompound, or mixture of compounds, formed from ethoxylation of vegetableoil, wherein at least one chain of polyethylene glycol is covalentlybound to the vegetable oil. In some embodiments, the fatty acids mayhave between about twelve carbons to about eighteen carbons. In someembodiments, the amount of ethoxylation can vary from about 2 to about200, about 5 to 100, about 10 to about 80, about 20 to about 60, orabout 12 to about 18 of ethylene glycol repeat units. The vegetable oilmay be hydrogenated or unhydrogenated. Suitable vegetable oils include,but are not limited to castor oil, hydrogenated castor oil, sesame oil,corn oil, peanut oil, olive oil, sunflower oil, safflower oil, soybeanoil, benzyl benzoate, sesame oil, cottonseed oil, and palm oil. Othersuitable vegetable oils include commercially available synthetic oilssuch as, but not limited to, Miglyol™ 810 and 812 (available fromDynamit Nobel Chemicals, Sweden) Neobee™ M5 (available from DrewChemical Corp.), Alofine™ (available from Jarchem Industries), theLubritab™ series (available from JRS Pharma), the Sterotex™ (availablefrom Abitec Corp.), Softisan™ 154 (available from Sasol), Croduret™(available from Croda), Fancol™ (available from the Fanning Corp.),Cutina™ HR (available from Cognis), Simulsol™ (available from CJPetrow), EmCon™ CO (available from Amisol Co.), Lipvol™ CO, SES, andHS-K (available from Lipo), and Sterotex™ HM (available from AbitecCorp.). Other suitable vegetable oils, including sesame, castor, corn,and cottonseed oils, include those listed in R. C. Rowe and P. J.Shesky, Handbook of Pharmaceutical Excipients, (2006), 5th ed., which isincorporated herein by reference in its entirety. Suitablepolyethoxylated vegetable oils, include but are not limited to,Cremaphor™ EL or RH series (available from BASF), Emulphor™ EL-719(available from Stepan products), and Emulphor™ EL-620P (available fromGAF).

Mineral oils: As used herein, the term “mineral oil” refers to bothunrefined and refined (light) mineral oil. Suitable mineral oilsinclude, but are not limited to, the Avatech™ grades (available fromAvatar Corp.), Drakeol™ grades (available from Penreco), Sirius™ grades(available from Shell), and the Citation™ grades (available from AvaterCorp.).

Castor oils: As used herein, the term “castor oil,” refers to a compoundformed from the ethoxylation of castor oil, wherein at least one chainof polyethylene glycol is covalently bound to the castor oil. The castoroil may be hydrogenated or unhydrogenated. Synonyms for polyethoxylatedcastor oil include, but are not limited to polyoxyl castor oil,hydrogenated polyoxyl castor oil, mcrogolglyceroli ricinoleas,macrogolglyceroli hydroxystearas, polyoxyl 35 castor oil, and polyoxyl40 hydrogenated castor oil. Suitable polyethoxylated castor oilsinclude, but are not limited to, the Nikkol™ HCO series (available fromNikko Chemicals Co. Ltd.), such as Nikkol HCO-30, HC-40, HC-50, andHC-60 (polyethylene glycol-30 hydrogenated castor oil, polyethyleneglycol-40 hydrogenated castor oil, polyethylene glycol-50 hydrogenatedcastor oil, and polyethylene glycol-60 hydrogenated castor oil,Emulphor™ EL-719 (castor oil 40 mole-ethoxylate, available from StepanProducts), the Cremophore™ series (available from BASF), which includesCremophore RH40, RH60, and EL35 (polyethylene glycol-40 hydrogenatedcastor oil, polyethylene glycol-60 hydrogenated castor oil, andpolyethylene glycol-35 hydrogenated castor oil, respectively), and theEmulgin® RO and HRE series (available from Cognis PharmaLine). Othersuitable polyoxyethylene castor oil derivatives include those listed inR. C. Rowe and P. J. Shesky, Handbook of Pharmaceutical Excipients,(2006), 5th ed., which is incorporated herein by reference in itsentirety.

Sterol: As used herein, the term “sterol” refers to a compound, ormixture of compounds, derived from the ethoxylation of sterol molecule.Suitable polyethoyxlated sterols include, but are not limited to, PEG-24cholesterol ether, Solulan™ C-24 (available from Amerchol); PEG-30cholestanol, Nikkol™ DHC (available from Nikko); Phytosterol, GENEROL™series (available from Henkel); PEG-25 phyto sterol, Nikkol™ BPSH-25(available from Nikko); PEG-5 soya sterol, Nikkol™ BPS-5 (available fromNikko); PEG-10 soya sterol, Nikkol™ BPS-10 (available from Nikko);PEG-20 soya sterol, Nikkol™ BPS-20 (available from Nikko); and PEG-30soya sterol, Nikkol™ BPS-30 (available from Nikko).

Polyethylene glycol: As used herein, the term “polyethylene glycol” or“PEG” refers to a polymer containing ethylene glycol monomer units offormula —O—CH₂—CH₂—. Suitable polyethylene glycols may have a freehydroxyl group at each end of the polymer molecule, or may have one ormore hydroxyl groups etherified with a lower alkyl, e.g., a methylgroup. Also suitable are derivatives of polyethylene glycols havingesterifiable carboxy groups. Polyethylene glycols useful in the presentinvention can be polymers of any chain length or molecular weight, andcan include branching. In some embodiments, the average molecular weightof the polyethylene glycol is from about 200 to about 9000. In someembodiments, the average molecular weight of the polyethylene glycol isfrom about 200 to about 5000. In some embodiments, the average molecularweight of the polyethylene glycol is from about 200 to about 900. Insome embodiments, the average molecular weight of the polyethyleneglycol is about 400. Suitable polyethylene glycols include, but are notlimited to polyethylene glycol-200, polyethylene glycol-300,polyethylene glycol-400, polyethylene glycol-600, and polyethyleneglycol-900. The number following the dash in the name refers to theaverage molecular weight of the polymer. In some embodiments, thepolyethylene glycol is polyethylene glycol-400. Suitable polyethyleneglycols include, but are not limited to the Carbowax™ and Carbowax™Sentry series (available from Dow), the Lipoxol™ series (available fromBrenntag), the Lutrol™ series (available from BASF), and the Pluriol™series (available from BASF).

Propylene glycol fatty acid ester: As used herein, the term “propyleneglycol fatty acid ester” refers to a monoether or diester, or mixturesthereof, formed between propylene glycol or polypropylene glycol and afatty acid. Fatty acids that are useful for deriving propylene glycolfatty alcohol ethers include, but are not limited to, those definedherein. In some embodiments, the monoester or diester is derived frompropylene glycol. In some embodiments, the monoester or diester hasabout 1 to about 200 oxypropylene units. In some embodiments, thepolypropylene glycol portion of the molecule has about 2 to about 100oxypropylene units. In some embodiments, the monoester or diester hasabout 4 to about 50 oxypropylene units. In some embodiments, themonoester or diester has about 4 to about 30 oxypropylene units.Suitable propylene glycol fatty acid esters include, but are not limitedto, propylene glycol laurates: Lauroglycol™ FCC and 90 (available fromGattefosse); propylene glycol caprylates: Capryol™ PGMC and 90(available from Gatefosse); and propylene glycol dicaprylocaprates:Labrafac™ PG (available from Gatefosse).

Stearoyl macrogol glyceride: Stearoyl macrogol glyceride refers to apolyglycolized glyceride synthesized predominately from stearic acid orfrom compounds derived predominately from stearic acid, although otherfatty acids or compounds derived from other fatty acids may be used inthe synthesis as well. Suitable stearoyl macrogol glycerides include,but are not limited to, Gelucire® 50/13 (available from Gattefossé).

In some embodiments, the diluent component comprises one or more ofmannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powderedcellulose, microcrystalline cellulose, carboxymethylcellulose,carboxyethylcellulose, methylcellulose, ethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodiumstarch glycolate, pregelatinized starch, a calcium phosphate, a metalcarbonate, a metal oxide, or a metal aluminosilicate.

Exemplary excipients or carriers for use in solid and/or liquid dosageforms include, but are not limited to:

Sorbitol: Suitable sorbitols include, but are not limited to,PharmSorbidex E420 (available from Cargill), Liponic 70-NC and 76-NC(available from Lipo Chemical), Neosorb (available from Roquette),Partech SI (available from Merck), and Sorbogem (available from SPIPolyols).

Starch, sodium starch glycolate, and pregelatinized starch include, butare not limited to, those described in R. C. Rowe and P. J. Shesky,Handbook of Pharmaceutical Excipients, (2006), 5th ed., which isincorporated herein by reference in its entirety.

Disintegrant: The disintegrant may include one or more of croscarmellosesodium, carmellose calcium, crospovidone, alginic acid, sodium alginate,potassium alginate, calcium alginate, an ion exchange resin, aneffervescent system based on food acids and an alkaline carbonatecomponent, clay, talc, starch, pregelatinized starch, sodium starchglycolate, cellulose floc, carboxymethylcellulose,hydroxypropylcellulose, calcium silicate, a metal carbonate, sodiumbicarbonate, calcium citrate, or calcium phosphate.

Still further embodiments of the invention include the active agentadministered in combination with other active such as, for example,adjuvants, protease inhibitors, NSAIDs, steroid anti-inflammatory drugs(SAIDs), or other compatible drugs or compounds where such combinationis seen to be desirable or advantageous in achieving the desired effectsof the methods described herein.

Other embodiments of the present invention include a pharmaceuticalcomposition comprising an effective amount of the active agent and oneor more pharmaceutically acceptable excipient. Other embodiments includea pharmaceutical composition comprising an effective amount ofpharmaceutically-acceptable salts of the active agent. Other embodimentsinclude a pharmaceutical composition comprising an effective amount ofpharmaceutically-acceptable salts of active agent and apharmaceutically-acceptable excipient.

In yet other embodiments, the active agent may be combined with one ormore secondary therapeutic agents. Secondary therapeutic agents myinclude but are not limited to: an anti-platelet agent, an inhibitor ofangiotensin II, an ACE inhibitor, a Ca′ channel blocker, an insulinsensitizer, a HMG-CoA reductase inhibitor, a beta blocker, anon-steroidal anti-inflammatory drug, a steroidal anti-inflammatorydrug, peroxisome proliferator-activated receptors (PPAR) modulators, andcombinations thereof.

Nitroalkene NSAID compositions as described herein may be administeredto subjects to treat a number of both acute and chronic inflammatory andmetabolic conditions. In some embodiments, the compounds within thescope of the described invention and pharmaceutical compositions thereofas described herein may be used to treat inflammation relatedconditions, including but not limited to, autoimmune disease,auto-inflammatory disease, arterial stenosis, organ transplant rejectionand burns, and chronic conditions such as, chronic lung injury andrespiratory distress, diabetes, hypertension, obesity, arthritis,atherosclerosis, asthma, gouty arthritis, kidney diseases, lupus,inflammatory diseases of the system central nervous system (CNS),neurodegenerative disorders, and various skin disorders.

However, in other embodiments, the nitroalkene NSAID compounds andpharmaceutical compositions thereof as described herein may be used totreat any condition having symptoms including chronic or acuteinflammation, such as, for example, arthritis, lupus, Lyme's disease,gout, sepsis, hyperthermia, ulcers, enterocolitis, osteoporosis, viralor bacterial infections, cytomegalovirus, periodontal disease,glomerulonephritis, sarcoidosis, lung disease, lung inflammation,fibrosis of the lung, asthma, acquired respiratory distress syndrome,tobacco induced lung disease, granuloma formation, fibrosis of theliver, graft vs. host disease, postsurgical inflammation, coronary andperipheral vessel restenosis following angioplasty, stent placement orbypass graft, coronary artery bypass graft (CABG), acute and chronicleukemia, B lymphocyte leukemia, neoplastic diseases, arteriosclerosis,atherosclerosis, myocardial inflammation, psoriasis, immunodeficiency,disseminated intravascular coagulation, systemic sclerosis, amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, encephalomyelitis, edema, inflammatory bowel disease, hyper IgEsyndrome, cancer metastasis or growth, adoptive immune therapy,reperfusion syndrome, radiation burns, alopecia and the like.

The compounds within the scope of the described invention andpharmaceutical compositions thereof as described herein may beadministered to subjects to treat inflammation related conditions suchas, but not limited to, CIDs.

General Synthetic Procedures

In general, the synthetic route by which the nitroalkene NSAIDs areobtained starts with the formylation of an NSAID aromatic ring followedby a condensation reaction of the prepared aldehyde with a nitroalkane.

One such synthetic route follows the following steps:

The scheme depicted above demonstrates a process of formylating aromaticcompounds with hexamethylenetetramine (“HMTA”) and trifluoroacetic acid(“TFA”) followed by a base-catalyzed condensation reaction of thealdehyde (“NSAID-CHO”) with a nitroalkane (“R—NO₂”) in glacial aceticacid (“AcOH”) to produce the desired nitroalkene NSAID (“NA-NSAID”).Although various weak bases and nitroalkanes of various carbon lengthscan be used, the preferred nitroalkane and weak base are nitromethaneand ammonium acetate, respectively, as shown infra. When thecorresponding aldehyde is commercially available, it is not necessary toperform step 1. Another procedure for the synthesis of nitroalkene NSAIDis illustrated in Example 2 below. It is well within the knowledge andskill of a person of ordinary skill in the art to prepare the aldehydeand perform the subsequent condensation reaction to synthesizenitroalkene NSAIDs.

EXAMPLES

The following examples contain detailed methods of preparing compoundswithin the scope of the present invention. These detailed descriptionsserve to exemplify the above general synthetic schemes which form partof the invention. These detailed descriptions are presented forillustrative purposes only and are not intended as a restriction on thescope of the invention. All parts are by weight and temperatures are inDegrees Celsius unless otherwise indicated. All compounds showed NMRspectra consistent with their assigned structures.

Example 1 (E)-N-(4-hydroxy-3-(2-nitrovinyl)phenyl)acetamide (PARANA)

N-(3-formyl-4-hydroxyphenyl)acetamide

To a solution of N-(4-hydroxyphenyl)acetamide (6.6 mmol) in TFA (4 mL),in an ice-bath, HMTA (26 mmol) was added portion-wise. The reactionmixture is heated to 70° C. for 5 h, allowed to cool to room temperature(rt) and poured into water (20 mL). Then, it was extracted with ethylacetate (3×20 mL). The combined organic extracts were washed with brineand dried over sodium sulfate. The crude product was purified by silicaflash column chromatography (hexane:ethyl acetate, 1:1) to render thedesire product (133 mg, 11%). ¹H NMR (400 MHz, acetone-d6) δ 10.73 (s,1H), 10.01 (s, 1H), 9.24 (s, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.70 (dd,J=8.9, 2.7 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 2.09 (s, 3H).

(E)-N-(4-hydroxy-3-(2-nitrovinyl)phenyl)acetamide

To a solution of N-(3-formyl-4-hydroxyphenyl)acetamide (0.18 mmol) innitromethane (0.1 mL) is added glacial acetic acid (0.1 mL) and ammoniumacetate (0.11 mmol). The solution is heated at 110° C. for 1 hour.Ice-water is added to the reaction mixture, and then extracted withethyl acetate, dried over sodium sulfate and concentrated under reducedpressure to give the desire product with high purity (32 mg, 80%). ¹HNMR (400 MHz, acetone-d6) δ 9.66 (s, 1H); 9.14 (s, 1H); 8.16 (d, J=13.5Hz, 1H); 8.01 (d, J=13.5 Hz, 1H); 7.88 (d, J=2.3 Hz, 1H); 7.62 (dd,J=2.3, 8.8 Hz, 1H); 7.00 (d, J=8.8 Hz, 1H); 2.06 (s, 3H). ¹³C NMR (100MHz, acetone-d6) δ 167.84, 153.93, 138.03, 135.20, 132.55, 125.17,122.22, 117.03, 116.37, 23.11.

Example 2 (E)-2-(4-isobutyl-3-(2-nitrovinyl)phenyl)propanoic Acid(IBUNA)

2-(3-formyl-4-isobutylphenyl)propanoic Acid

Ibuprofen (4.8 mmol) was dissolved in dry DCM (13 mL), purged with N₂,and cooled with an ice bath to 0° C. A solution of TiCl₄ 1.0 M in DCM(21.5 mL) was added dropwise. The reaction mixture was stirred for 1 h.Then, dichloromethyl methyl ether (1 mL) was added, and the mixture wasleft to react for 4 h. Next, 40 mL of a saturated solution of NH₄Cl wasadded and left stirring for 2 h. The organic layer was separated andwashed with 0.1 N HCl solution (15 mL) and brine (15 mL). The organiclayer was dried over sodium sulfate and filtered, and the solvent wasevaporated under reduced pressure. The crude product was purified bysilica flash column chromatography (ethyl acetate:hexane gradient) togive the desired product (123 mg, 11%). ¹H NMR (400 MHz, CDCl₃) δ 10.30(s, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.49 (dd, J=7.9, 2.1 Hz, 1H), 7.23 (d,J=7.9 Hz, 1H), 3.82 (q, J=7.2 Hz, 1H), 2.89 (d, J=7.2 Hz, 2H), 1.90-1.80(m, 1H), 1.56 (d, J=7.2 Hz, 3H), 0.96 (s, 3H), 0.94 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 191.97, 179.21, 143.80, 138.18, 134.12, 132.73,132.31, 129.88, 44.66, 40.86, 31.17, 22.36, 18.03.

(E)-2-(4-isobutyl-3-(2-nitrovinyl)phenyl)propanoic Acid

To a solution of 2-(3-formyl-4-isobutylphenyl)propanoic acid (0.7 mmol)in nitromethane (1 mL) is added glacial acetic acid (3 mL) and ammoniumacetate (2.1 mmol). The solution is heated at 110° C. for 4.5 hours.Ice-water is added to the reaction mixture, and then extracted withethyl acetate, dried over sodium sulfate and concentrated under reducedpressure. The crude product was purified by silica flash columnchromatography (ethyl acetate:hexane gradient) to give the desireproduct (97 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=13.5 Hz, 1H),7.54 (d, J=13.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.39 (dd, J=7.8, 1.8Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 3.77 (q, J=7.2 Hz, 1H), 2.64 (d, J=7.2Hz, 2H), 1.86-1.76 (m, 1H), 1.56 (d, J=7.2 Hz, 3H), 0.96 (s, 3H), 0.94(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 179.65, 142.31, 138.32, 137.84,136.59, 131.93, 130.85, 129.00, 126.33, 44.75, 42.18, 30.78, 22.36,18.08. MS (EI, 70 eV): m/z (%) 277 (M+, 6).

Example 3(E)-5-(2-nitrovinyl)-2-((3-(trifluoromethyl)phenyl)amino)benzoic acid(FluFENA)

5-formyl-2-((3-(trifluoromethyl)phenyl)amino)benzoic Acid

To a solution of flufenamic acid (18 mmol) in TFA (0.5 mL), in anice-bath, HMTA (7 mmol) was added portionwise. The reaction mixture isheated to 70° C. for 5 h, allowed to cool to rt and poured into water(15 mL). Then, it was extracted with ethyl acetate (3×15 mL). Thecombined organic extracts were washed with brine and dried over sodiumsulfate. The crude product was purified by silica flash columnchromatography (hexane:ethyl acetate, 8:2) to render the desire product(298 mg, 54%). ¹H NMR (400 MHz, acetone-d6) δ 10.41 (s, 1H), 9.88 (s,1H), 8.59 (d, J=1.8 Hz, 1H), 7.95 (dd, J=8.8, 1.8 Hz, 1H), 7.70 (m, 3H),7.57 (m, 1H), 7.37 (dd, J=8.8 Hz, 1H). ¹³C NMR (100 MHz, acetone-d6) δ189.36, 169.08, 151.90, 140.26, 135.86, 134.12, 130.69, 127.29, 127.01,121.41, 121.37, 119.99, 119.95, 113.61.

(E)-5-(2-nitrovinyl)-2-((3-(trifluoromethyl)phenyl)amino)benzoic Acid

To a solution of 5-formyl-2-((3-(trifluoromethyl)phenyl)amino)benzoicacid (1 mmol) in nitromethane (1 mL) is added glacial acetic acid (4 mL)and ammonium acetate (2.9 mmol). The solution is heated at 110° C. for3.5 hours and allowed to cool to rt. An orange precipitate appear oncooling, was filtered-off and washed with water and dried to give thedesired product with high purity (264 mg, 78%). ¹H NMR (400 MHz,DMSO-d6) δ 13.57 (s, 1H), 10.22 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.13(d, J=13.5 Hz, 1H), 8.09 (d, J=13.5 Hz, 1H), 7.94 (dd, J=8.9, 1.9 Hz,1H), 7.64 (m, 3H), 7.50 (m, 1H), 7.23 (d, J=8.9 Hz, 1H). ¹³C NMR (100MHz, DMSO-d6) δ 169.62, 149.54, 140.71, 139.55, 136.23, 135.72, 134.86,131.19, 131.00, 130.69, 126.62, 125.75, 123.04, 121.09, 120.43, 119.37,114.83, 114.00. MS (EI, 70 eV): m/z (%) 352 (M+, 100).

Example 4 (E)-4-(2-nitrovinyl)benzoic Acid (BANA)

To a stirred solution of ammonium acetate (32 mmol), nitromethane (20mL) and glacial acetic acid (39 mL) at 90° C., 4-formylbenzoic acid (26mmol) was added portionwise and maintain at 90° C. for 5 hours. Then,the reaction mixture was allowed to cool to rt. A yellow precipitateappear on cooling, was filtered-off and washed with water and dried togive the desired product with high purity (3.93 g, 78%). ¹H NMR (400MHz, CDCl₃) δ 8.30 (d, J=13.7 Hz, 1H), 8.18 (d, J=13.7 Hz, 1H), 8.00 (d,J=8.6 Hz, 2H), 7.97 (d, J=8.6 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ167.07, 140.12, 138.30, 134.88, 133.80, 130.30 (2C), 130.26 (2C).

Example 5 (E)-4-(2-nitrovinyl)phenol (PheNA)

An analogous procedure as shown in Example 4 is performed with4-hydroxybenzaldehyde to produce (E)-4-(2-nitrovinyl)phenol as a yellowsolid (yield 68%). ¹⁻H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.04 (d,J=13.5 Hz, 1H), 7.84 (d, J=13.5 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 6.97(d, J=8.6 Hz, 1H).

Biologic Activity

The following methods described are used in order to demonstratebiological activity and therapeutic use, and should not to be construedin any way as limiting the scope of the invention. While not wishing notto be bound by theory, the generation of the low grade, sterile, chronicinflammatory state underlying CIDs is the activation of thepro-inflammatory transcription factor NF-κB and the inflammasome (acytosolic supramolecular platform responsible of the production ofinterleukin (IL) 1β and 18 (IL1β, IL18)). The following studiesdemonstrate the role of nitroalkene NSAIDs in reducing thepro-inflammatory activity regulated by NF-κB and the inflammasome.

In Vitro Activity

While not wishing to be bound by theory, during inflammation, reversiblereactions with nucleophilic molecules such as NF-κB and theinflammasomes have shown to modify inflammatory response. One method toidentify reactions with nucleophilic targets at physiological pH is byscreening with beta mercaptoethanol (“BME”). As shown in FIGS. 1-4,nitroalkene NSAIDs form adducts with beta mercaptoethanol (“BME”), Thereactions demonstrating nitroalkene NSAID adduction to BME depicted byFIGS. 1-5 included reacting 30 μM of PARANA with 30 μM of BME in 100 mMphosphate buffer at pH 7.4, 50 μM of IBUNA with 250 μM of BME in 100 mMphosphate buffer at pH 7.4, 12.5 μM FluFENA with 125 μM BME in 100 mMphosphate buffer at pH 7.4, 10 μM of BANA with 30 μM of BME in 100 mM ofphosphate buffer at pH 7.4, and 50 μM of PheNA with 500 μM of BME in 100mM phosphate buffer at pH 7.4. All reactions showed an absorbanceincrease which denoted nitroalkene NSAID adduction with BME. Thus, thenitroalkene NSAIDs within the scope of the present invention react withnucleophilic molecules such as NF-κB and the inflammasomes to modifyinflammatory response.

Further in vitro studies demonstrated the unexpected advantage of thenitroalkene NSAIDs over non-nitroalkenylated NSAIDs to downregulatesecretion of pro-inflammatory cytokines. In order to compare benzoicacid (BA) and nitroalkene benzoic acid (BANA) over NF-κB andinflammasome function in macrophages, THP-1 cells were differentiatedinto macrophages with PMA (200 nM, 48 h). Cells were then stimulatedwith LPS (250 ng/mL) and with ATP (5 mM, 45 minutes). Together with LPS(1st signal, FIG. 6) or ATP (2nd signal, FIG. 7), cells were treatedwith Benzoic acid (30 μM) or BANA (30 μM). Supernatants were collectedand IL-1β secretion was measured by ELISA. According to the results, theinhibition of IL-1β secretion in cells stimulated by LPS demonstratedthe ability of BANA to prevent NF-κB nuclear translocation, which is acrucial step in the generation of the inflammasome. The inhibition ofIL-1β secretion in cells stimulated by ATP demonstrated the directinhibition of the inflammasome. Thus, BANA inhibits both the generationof the inflammasome, and inhibits the inflammasome itself.

Further exemplary studies were performed with Flufenamate (FluFE) andnitroalkene flufenamate (FluFENA). In order to study the effect ofFlufenamate (FluFE) and FluFENA over NF-κB and inflammasome function inmacrophages, THP-1 cells were differentiated into macrophages with PMA(200 nM, 48 h). Cells were stimulated with LPS (250 ng/mL) and then withATP (5 mM, 45 minutes). Together with LPS (1st signal, FIG. 8) or ATP(2nd signal, FIG. 9), cells were treated with FluFE (5 μM) or FluFENA (5μM). Supernatant were collected and IL-1β secretion was measured byELISA. Cell viability was assessed by the MTT assay. Again, theresulting data demonstrates the unexpected advantage provided by thenitroalkene NSAID.

FIG. 10 and FIG. 11 further demonstrate the unexpected superiority ofnitroalkene NSAIDs of non-alkenylated NSAIDs. To study the effect ofibuprofen and IBUNA over NF-κB and inflammasome function in macrophages,THP-1 cells were differentiated into macrophages with PMA (200 nM, 48h). Cells were stimulated with LPS (250 ng/mL) and then with ATP (5 mM,45 minutes). Together with LPS (1st signal, FIG. 10) or ATP (2nd signal,FIG. 11), cells were treated with Ibuprofen (20 μM) or IBUNA (20 μM).Supernatant were collected and IL-1β secretion was measured by ELISA.

In Vivo Activity

Unexpected superior anti-inflammatory effects of nitroalkene NSAIDs werefurther demonstrated by in vivo models. For example, FIG. 12demonstrates the anti-inflammatory effects of BA or BANA in an in vivomodel of peritonitis. Mice were treated with BANA, Benzoic Acid (50mg/kg, IP) or the vehicle (100 mM Phosphate buffer 10% DMSO) for 1 hour.Then were injected with LPS (10 mg/kg, IP) or PBS for 2 hours. Mice werecollected for peritoneal wash and blood samples were extracted. Theperitoneal wash and plasma were stored to measure IL-1β by ELISA. Thevalues are show as mean±SD from three mice per condition and we haveused the statistic test one-way ANOVA with Bonferroni. FIG. 11illustrates a marked decrease in the level of pro-inflammatory cytokineIL-1β secretion in mice treated with BANA as opposed to BA in both theblood plasma and the peritoneal wash.

The invention claimed is:
 1. A compound of Formula I:

wherein R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1, wherein the compound ofFormula I is

or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a compound of claim 1 and a carrier.
 4. Acompound of Formula II:

wherein R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.
 5. The compound of claim 4, wherein the compound ofFormula II is

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound of claim 4 and a carrier.
 7. Acompound of Formula III:

wherein R is hydrogen or a C₁₋₁₁ alkyl, or a pharmaceutically acceptablesalt thereof.
 8. The compound of claim 7, wherein the compound ofFormula III is

or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a compound of claim 7 and a carrier.